Use of Platelet Rich Fibrin (PRF)-Based Autologous Membranes for Tooth Extraction in Patients Under Bisphosphonate Therapy: a Case Report

biomedicines

Case Report Use of Platelet Rich Fibrin (PRF)-Based Autologous Membranes for Tooth Extraction in Patients under Bisphosphonate Therapy: A Case Report

Alberto Pispero , Ivan Bancora, Antonious Khalil, Dario Scarnò and Elena M. Varoni *

Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, University of Milan, Via Beldiletto 1, 20142 Milano, Italy; [email protected] (A.P.); [email protected] (I.B.); [email protected] (A.K.); [email protected] (D.S.) * Correspondence: [email protected]; Tel.: +39-0250319017

Received: 25 September 2019; Accepted: 2 November 2019; Published: 10 November 2019

Abstract: Tooth extraction in patients treated with bisphosphonates (BPs) for osteoporosis or cancer exposes the patient to the risk of osteonecrosis of the jaw. An autologous membrane using platelet-rich fibrin (PRF) is an innovative technique to promote wound healing, which allows obtaining a hermetic closure of the post-extractive surgical site without the need of mucoperiosteal flaps or periosteal releasing incisions. Here, we report the case of a 70-year-old woman, in therapy with alendronate for 12 years, requiring the upper right premolar extraction because of a crown fracture. After the tooth extraction performed under antiseptic and antibiotic coverage, the PRF autologous membrane was placed on the surgical wound to close completely the post-extraction site. Follow-up visits were carried out after one, two, four weeks and two months from the intervention. The complete re-epithelization of the wound was observed without signs of infection. The use of PRF for the closure of post-extraction sockets in patients taking BPs appears to be a promising alternative to the more invasive surgical procedures. Future clinical trials will be pivotal in elucidating the effectiveness of PRF to prevent BP-related osteonecrosis after tooth extraction.

Keywords: oral medicine; oral surgery; bisphosphonates; platelet-rich ﬁbrin; osteonecrosis

1. Introduction Bisphosphonates (BPs) and denosumab are bone antiresorptive agents, commonly prescribed for treating disorders of bone metabolism [1–3]. BPs at high dosage are useful in managing cancer metastases and other malignant diseases, including multiple myeloma; they are also prescribed at low dosage for the treatment of systemic conditions such as osteoporosis and Paget’s disease. These drugs have diﬀerent mechanisms of action to reduce bone resorption via blockage of osteoclast diﬀerentiation: BPs act at an osteoclast level, while denosumab inhibits RANK-L. A strong correlation between the use of these drugs and the risk of osteonecrosis of the jaws has been well documented in the literature, especially after a local trauma, mainly as tooth extraction [4,5]. This complication is characterized by an intraoral persistent area of bone exposure and/or signs of infection for a minimum period of 8 weeks that occurs in patients who are under current or previous treatment with BPs or other anti-resorbing drugs, without a clinical history of the head/neck radiotherapy [4,6,7]. Since the number of patients who have taken or are taking BPs is increasing in dental practice, a preventive approach, before starting BPs or denosumab therapies, is strongly recommended, in order to eliminate preliminarily the hopeless teeth and to treat dental foci of infection, thus avoiding the need of tooth extraction once the therapy has been commenced [8]. Rarely, the osteonecrosis has

Biomedicines 2019, 7, 89; doi:10.3390/biomedicines7040089 www.mdpi.com/journal/biomedicines Biomedicines 2019, 7, 89 2 of 8 been associated with a local trauma due to the presence of incongruous removable prostheses, bone exostosis or to the insertion of dental implants [9]. The risk of developing osteonecrosis is related to the route of drug administration and dosage. More than 90% of cases reported in the literature are related to the intravenous use of zoledronic or pamidronic acid, usually prescribed for treating cancers affecting bone tissue. Zoledronate, in particular, is most frequently agent associated with osteonecrosis of the jaw, with a risk of 1% in the first year of intake to reach 21% after 3 years from the first administration. Patients taking other types of BPs, such as alendronate per os and at lower dosage for osteoporosis, however, are not exempted from the risk. The administration of systemic antibiotics in association with oral antiseptics in the pre- and/or post-surgical phases, the execution of atraumatic extraction procedures and the mobilization of mucoperiosteal flaps for primary closure of the surgical site are standard procedures of safety to prevent osteonecrosis in BP patients requiring oral surgery [3,9]. Neither international consensus nor the duration of the administration is available for which types of antibiotics should be used. Several protocols have been proposed, in particular using broad-spectrum antibiotics such as amoxicillin (1 g, 3 times/day) with or without clavulanic acid, also in combination with metronidazole (500 mg, 2 times/day), in case of allergy to penicillin, erythromycin (600 mg, 3 times/day), clindamycin (600 mg, 3 times/day) or ciprofloxacin (500 mg, 2 times/day). Lodi et al. proposed a protocol based on a combined antibiotic and antiseptic therapy that starts 3 days before surgery and continues for at least a week, and could be prolonged according to progress of the wound healing [9,10]. Intra-operative primary wound closure is, in this protocol, recommended to reduce bone infection [9,10], thus requiring mucoperiosteal flaps or periosteal releasing incisions and a more invasive procedure. To date, biomaterial-based alternatives are pivotal in closing the surgical site with minimal invasiveness. In the present case report, we have investigated the use of platelet-rich fibrin (PRF) for this purpose. PRF, developed by Joseph Choukroun for uses in oral and maxillofacial surgery [11–13], is currently the most commonly studied platelet concentrate to facilitate the healing of post-extraction sockets. The preparation of PRF does not require the use of anticoagulants (bovine thrombin), as occurs for other platelet concentrates, such as platelet-rich plasma (PRP) and growth factors-rich plasma (PRGF). PRF is strictly autologous, producing negligible minimal immunological reaction and containing a mixture of patient-derived platelets, leukocytes, growth factors and cytokines. Two of the main advantages are related to the ease in manufacturing and the presence of bioactive elements. PRF requires, indeed, a single-step manufacturing procedure, where the autologous blood sample necessitates minimum blood manipulation [14]. PRF can be produced following fast and simple steps for collection and preparation, and patient’s blood can be drawn via a vacutainer before, during or after the surgical intervention. From a clinical point of view, PRF shows excellent handling properties, including resistance to traction and elasticity, and it can be easily sutured in a surgically selected position, even in combination with bone grafts [14,15]. Regarding bioactive elements, a plethora of growth factors and cytokines can be released from PRF constantly and steadily in the long term [15]. PRF includes transforming growth factor-beta 1 (TGF-β1), platelet-derived growth factor-BB (PDGF), insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factors (VEGFs), as well as interleukin (IL)-1β, IL-4 and IL-6 [14]. The resulting three-dimensional PRF-based membrane/scaffold promotes tissue regeneration, and it can also act as functional support for the bone morphogenetic proteins (BMPs), from which osteoconductive properties can be further derived [9–12,16]. Here, we reported the successful case of a patient requiring dental extraction of a hopeless fractured tooth, who received BP therapy based on alendronate for 12 years. The surgical procedure, under antiseptic and antibiotic coverage, was performed by placing an autologous PRF membrane to close the post-extraction site. Biomedicines 2019, 7, 89 3 of 8

2. Description of the Case

BiomedicinesThe patient, 2019, 7, xa FOR 70-year-old PEER REVIEW woman with glaucoma and osteoporosis, came to our observation3 dueof 8 Biomedicinesto the suspected 2019, 7, x fracture FOR PEER of REVIEW upper right second premolar (1.5 teeth). In her clinical history, she reported3 of 8 previousThe intra-oral and current examination therapies with showed alendronate the upper for right 12 years premolars (70 mg and tablets, molars to be(1.4, taken 1.5 and once 1.6 a week).teeth) The intra-oral examination showed the upper right premolars and molars (1.4, 1.5 and 1.6 teeth) prostheticallyThe intra-oral restored examination with gold showed ceramic the crowns upper (Figure right premolars 1). and molars (1.4, 1.5 and 1.6 teeth) prosthetically restored with gold ceramic crowns (Figure 1). prosthetically restored with gold ceramic crowns (Figure1).

Figure 1. Initial intra-oral clinical clinical view view of the suspected fracture of u upperpper right premolar (1.5 teeth) Figure 1. Initial intra-oral clinical view of the suspected fracture of upper right premolar (1.5 teeth) (quadrant I)I) of of a patient,a patient, showing showing the the premolars premolars and molarand molar (1.4, 1.5(1.4, and 1.5 1.6 and teeth) 1.6 prosthetically teeth) prosthetically restored (quadrant I) of a patient, showing the premolars and molar (1.4, 1.5 and 1.6 teeth) prosthetically withrestored gold-ceramic with gold-ceramic crowns. crowns. restored with gold-ceramic crowns. After gold ceramic crown removal, the fracture of upper right second premolar (1.5 teeth) was clinicallyAfter visible gold ceramic (Figure 2 crown2).). TheThe removal,toothtooth appearedappeared the fracture hopeless,hopeless, of upper andand thusthus right thethe second dentaldental premolar extractionextraction (1.5 waswas teeth) plannedplanned was clinicallyunder the visible patient’s (Figure agreement. 2). The tooth appeared hopeless, and thus the dental extraction was planned under the patient’s agreement.

Figure 2.2. Intra-oralIntra-oral clinical clinical picture picture after after the the crown crown removal, removal, showing showing the fracture the fracture of upper of rightupper second right Figurepremolarsecond 2.premolar (1.5Intra-oral teeth). (1.5 clinical teeth). picture after the crown removal, showing the fracture of upper right second premolar (1.5 teeth). Following the preventive protocol proposed by LodiLodi etet al.al. to to reduce the risk of BP-related osteonecrosisFollowing of the the preventive jaw, the patient protocol underwent proposed a professionalpr ofessionalby Lodi et oral al. hygieneto reduce session the risk a week of BP-related before the osteonecrosisextraction, alsoalso of starting startingthe jaw, a athe local local patient antiseptic antiseptic underwent therapy therap a withy pr withofessional 0.2% 0.2% chlorhexidine chlorhexidine oral hygiene mouthrinse session mouthrinse a week twice twice abefore day. a day. Thethe extraction,antibioticThe antibiotic therapy also therapy starting was was set a threelocal set three daysantiseptic days before before therap the intervention they with intervention 0.2% (amoxicillin chlorhexidine (amoxicillin 1 g tablets:mouthrinse 1 g tablets: 1 tablet 1 twice tablet every a every day. 8 h) Theto8 h) be antibioticto continued be continued therapy at least at was least for set one-week for three one-week days post-extraction before post-extraction the in [tervention9]. [9]. (amoxicillin 1 g tablets: 1 tablet every 8 h) toDuring be continued the day at of least the intervention,for one-week post-extractiona blood samplesample [9]. (20 mL) was drawn from the patient and collectedDuring in twothe day sterile of tubes,the intervention, without any a typetypeblood ofof sa anticoagulant.anticoagulant.mple (20 mL) The was PRFdrawn protocol from the was patient performed and collectedaccording in to two the Choukroun sterile tubes, procedure without any[17] [17] type and the theof anticoagulant.European European Directive Directive The PRF 2004/23/CE 2004 protocol/23/CE of of was 31 31 March Marchperformed 2004. 2004. accordingThe samplesample to was thewas centrifugedChoukroun centrifuged onceprocedure once at 3000at 3000 [17] rpm andrpm for the 10for min.European 10 min. At the At Directive end the of end the 2004/23/CE centrifugation,of the centrifugation, of 31 threeMarch distinct 2004.three Thefractionsdistinct sample fractions were was obtained: centrifugedwere obtained: at the once bottom atat the3000 of thebottom rpm tube, for theof 10the concentrated min. tube, At thethe red concentratedend cells of couldthe centrifugation, red be observed, cells could while,three be distinctatobserved, the top, fractions therewhile, was atwere the obtained: formationtop, there at ofwas the the the so-calledbottom format of platelet-poor ionthe oftube, the theso-called plasma. concentrated Theplatelet-poor intermediate red cells plasma. could part was,The be observed,instead,intermediate the while, dense part atwas, PRF the clot,instead, top, which there the can densewas be the then PRF format clinically clot, whichion usedof canthe in be theso-called then form clinically ofplatelet-poor an autologous used in plasma. the membrane form The of intermediate(Figurean autologous3). part membrane was, instead, (Figure the 3). dense PRF clot, which can be then clinically used in the form of an autologous membrane (Figure 3). Biomedicines 2019, 7, x FOR PEER REVIEW 4 of 8 Biomedicines 2019, 7, x FOR PEER REVIEW 4 of 8 Biomedicines 2019, 7, 89 4 of 8 Biomedicines 2019, 7, x FOR PEER REVIEW 4 of 8

Figure 3. Platelet-rich fibrin (PRF) obtained from the patient’s blood sample. Figure 3. Platelet-rich fibrin (PRF) obtained from the patient’s blood sample. Figure 3. Platelet-rich ﬁbrin (PRF) obtained from the patient’s blood sample. After intra-oralFigure local 3. Platelet-rich anesthesia fibrin via (PRF) tissue obtained infiltration from the (2% patient’s mepivacaine blood sample. mg/ml + 1:100,000 After intra-oral local anesthesia via tissue infiltration (2% mepivacaine mg/ml + 1:100,000 adrenalin),After intra-oralthe atraumatic local extraction anesthesia of viathe tissueresidual inﬁltration root of 1.5(2% tooth mepivacaine was performed. mg/ mlAfter+ irrigation1:100,000 adrenalin),After intra-oralthe atraumatic local extractionanesthesia of viathe residualtissue infiltration root of 1.5 (2%tooth mepivacaine was performed. mg/ml After + irrigation1:100,000 withadrenalin), a sterile the saline atraumatic solution extraction of the ofsurgical the residual site, rootthe revision of 1.5 tooth of wasthe post-extraction performed. After socket irrigation was withadrenalin), a sterile the salineatraumatic solution extraction of the of surgical the residual site, rootthe revisionof 1.5 tooth of wasthe post-extractionperformed. After socket irrigation was withperformed a sterile and saline the solutionresulting of exposed the surgical alveolar site, thebone revision was covered of the post-extraction with two layers socket of PRF was (Figure performed 4). performedwith a sterile and saline the resulting solution exposed of the alveolarsurgical bonesite, wasthe coveredrevision withof the two post-extraction layers of PRF (Figuresocket 4).was and the resulting exposed alveolar bone was covered with two layers of PRF (Figure4). performed and the resulting exposed alveolar bone was covered with two layers of PRF (Figure 4).

Figure 4. PRFPRF membrane obtained from the patient’s blood sample. Figure 4. PRF membrane obtained from the patient’s blood sample. The first ﬁrst layer ofFigure the PRF4. PRF membrane membrane was obtained placed from withinwi thethin patient’s an alveolar blood socket sample. (Figure 55),), whilewhile thethe secondThe layer first waslayer positioned of the PRF above membrane the alveolar was placed so socket,cket, wi with thin anthe alveolar margins socket located (Figure under 5), the while surgical the The first layer of the PRF membrane was placed within an alveolar socket (Figure 5), while the flapﬂapsecond and layer aa resorbableresorbable was positioned 6.06.0 suturesuture above (Figure (Figure the6 ) alveolar6) was was placed placed socket, for for stabilization.with stabilization. the margins The The complete located complete under wound wound the closure surgical closure of second layer was positioned above the alveolar socket, with the margins located under the surgical oftheflap the post-extraction and post-extraction a resorbable alveolar 6.0alveolar suture socket socket (Figure was was obtained 6) obtainedwas placed (Figures (Figures for5 stabilization. and 5 and6). 6). The complete wound closure offlap the and post-extraction a resorbable 6.0alveolar suture socket (Figure was 6) obtainedwas placed (Figures for stabilization. 5 and 6). The complete wound closure of the post-extraction alveolar socket was obtained (Figures 5 and 6).

Figure 5. InsertionInsertion of of the the first ﬁrst layer layer of of PRF memb membranerane inside the post-extraction socket. Figure 5. Insertion of the first layer of PRF membrane inside the post-extraction socket. Figure 5. Insertion of the first layer of PRF membrane inside the post-extraction socket. Biomedicines 2019, 7, x FOR PEER REVIEW 5 of 8 Biomedicines 2019, 7, x FOR PEER REVIEW 5 of 8 Biomedicines 2019, 7, 89 5 of 8 Biomedicines 2019, 7, x FOR PEER REVIEW 5 of 8

Figure 6. Placement of the second layer of PRF membrane over the first layer, in order to cover the Figure 6. Placement of the second layer of PRF membrane over the first layer, in order to cover the post-extractionFigure 6. Placement alveolar of thesocket. second The layeredges of of PRF the membrane were over placed the first under layer, the in ordermucosal to coverflaps and the Figurepost-extraction 6. Placement alveolar of the socket. second The layer edges of of PRF the membrane wereover theplaced first under layer, the in ordermucosal to coverflaps andthe suturedpost-extraction to the surrounding alveolar socket. gingiva. The edges of the membrane were placed under the mucosal flaps and post-extractionsutured to the surrounding alveolar socket. gingiva. The edges of the membrane were placed under the mucosal flaps and sutured to the surrounding gingiva. Thesutured antibiotic to the surrounding regime was gingiva. continued for 14 days after surgery, combined with application of 1% The antibiotic regime was continued for 14 days after surgery, combined with application of 1% chlorhexidineThe antibiotic gel three regime times was a continuedday at the surgical for 14 days site. after surgery, combined with application of 1% chlorhexidineThe antibiotic gel three regime times was a continuedday at the forsurgical 14 days site. after surgery, combined with application of 1% chlorhexidineAt a post-operative gel three times one-week a day follow-up, at the surgical no signs site. of infection or inflammation were visible and chlorhexidineAt a post-operative gel three times one-week a day follow-up, at the surgical no signs site. of infection or inflammation were visible and thereAt was a post-operativenew gingival tissue one-week formation, follow-up, which no partially signs of covered infection the or surgical inflammation site (Figure were visible7). and thereAt was a post-operative new gingival tissue one-week formation, follow-up, which no partially signs of coveredinfection the or surgicalinflammation site (Figure were visible 7). and there was new gingival tissue formation, which partially covered the surgical site (Figure7). there was new gingival tissue formation, which partially covered the surgical site (Figure 7).

Figure 7. Intra-oral clinical view after 1 week from thethe intervention.intervention. Partial re-epithelization can be Figure 7. Intra-oral clinical view after 1 week from the intervention. Partial re-epithelization can be observed over the alveolar socket. Figureobserved 7. Intra-oralover the alveolar clinical socket.view after 1 week from the intervention. Partial re-epithelization can be Theobserved residual over thesutures alveolar were socket. removed at the end ofof thethe secondsecond post-operativepost-operative week, when the completeThe re-epithelization residual sutures of were the surgical surgicalremoved site site at was wasthe achieved, achieved,end of the with with second newly newly post-operative regenerated regenerated mucosa mucosa week, (Figure (Figurewhen the 88).). completeThe residualre-epithelization sutures ofwere the surgicalremoved site at wasthe achieved,end of the with second newly post-operative regenerated mucosa week, (Figurewhen the 8). complete re-epithelization of the surgical site was achieved, with newly regenerated mucosa (Figure 8).

Figure 8. Intra-oralIntra-oral clinical clinical view view afte afterr 2 weeks 2 weeks from from the the intervention intervention,, showing showing that that complete complete re- epithelizationre-epithelizationFigure 8. Intra-oral was was visible clinical visible at the atview the surgical afte surgicalr 2post-extraction weeks post-extraction from the site. site.intervention , showing that complete re- Figureepithelization 8. Intra-oral was visible clinical at theview surgical after 2post-extraction weeks from the site. intervention , showing that complete re- epithelization was visible at the surgical post-extraction site. Biomedicines 2019, 7, 89 6 of 8 Biomedicines 2019, 7, x FOR PEER REVIEW 6 of 8

No signs of inﬂammation,inflammation, infectioninfection or or exposed exposed bone bone were were detectable detectable at at a post-operativea post-operative follow-up follow- upvisit visit after after 2 months 2 months (Figure (Figure9). 9).

Figure 9. CompleteComplete re-epithelization re-epithelization of the surgical site after 2 months from the intervention.

3. Discussion Discussion and and Conclusions Conclusions BP drugs, usually prescribed for osteoporosis, hypercalcemia or bone metastases when the risk of fractures and pain are severe and could affect affect patient’spatient’s quality of life, have the aim of inhibiting osteoclast activityactivity and and consequently consequently reduce reduce the bonethe remodeling.bone remodeling. After oral After surgery, oral thesurgery, BP mechanism the BP mechanismof action hinders of action the bonehinders wound the bone healing wound related healin tog the related traumatism to the traumatism caused, for instancecaused, for by instance a dental byextraction. a dental BPsextraction. are responsible BPs are ofresponsible nearly 60% of of nearly osteonecrosis 60% of ofosteonecrosis the jaws [3], of which the jaws in most [3], ofwhich cases in is mosttriggered of bycases dentoalveolar is triggered surgery. by dentoalveolar Many authors describedsurgery. clinicalMany authors and pharmacological described clinical protocols and to pharmacologicalminimize the risk protocols of developing to minimize osteonecrosis the risk [1 of,4 ,developing5,8,9]. osteonecrosis [1,4,5,8,9]. The benefits benefits of using PRF autologous membranes, in the healing of post-extraction sites and improvement of post-operative pain, have been documenteddocumented in the recentrecent yearsyears [[18,19].18,19]. PRF can stimulate thethe healing healing process process both both in termsin terms of bone of bone tissue tissue regeneration regeneration by promoting by promoting osteogenesis osteogenesis within withinthe post-extraction the post-extraction site and site in termsand in of terms soft tissueof softregeneration tissue regeneration by promoting by promoting re-epithelization re-epithelization [17,18]. [17,18].Furthermore, Furthermore, suturing suturing the PRF th membranee PRF membrane over the over extraction the extraction socket achievessocket achieves a complete a complete closure closureof the wound,of the wound, as recommended as recommended in case in case of tooth of toot extractionh extraction in in BP BP patients patients to to minimizeminimize bacterial contamination [[9].9]. The latterlatter cancan bebe achievedachieved without without the the need need of of performing performing mucoperiosteal mucoperiosteal flaps flaps or orreleases releases of theof the periosteum periosteum that that could could increase increase the patient’sthe patient’s post-operative post-operative morbidity. morbidity. The useThe ofuse PRF, of PRF,thus, reducesthus, reduces invasiveness invasiveness of the surgicalof the procedure,surgical procedure, which is limitedwhich tois thelimited atraumatic to the extraction atraumatic of extractionthe tooth. of the tooth. Within the limitations of this case report (one patient receiving a single tooth extraction, who assumed BPs BPs per per os os for for osteoporosis), osteoporosis), the the use use of PRF of PRF membrane, membrane, as an as adjuvant an adjuvant for soft for and soft hard and tissuehardtissue healing, healing, appears appears promising promising to achieve to achieve the complete the complete closure closure of post-extraction of post-extraction sockets sockets with withmini-invasiveness. mini-invasiveness. Moreover, Moreover, the handling the handling properties properties of PRF membrane, of PRF membrane, which was which easy wasto be easyplaced to andbe placed used, were and used, clinically were excellent, clinically showing excellent, resist showingance and resistance adaptability and adaptabilityto the surgical to thewound surgical and woundelasticity, and such elasticity, as providing such as surgeons providing with surgeons a suitab withle and a suitablesimple positioning and simple during positioning the intervention during the [20,21].intervention PRF can [20 ,be21 ].proposed PRF can as be a proposedvalid alternative as a valid to traditional alternative surgical to traditional extraction surgical techniques extraction that involvetechniques mucoperiosteal that involve mucoperiostealflaps and periosteal flaps releases, and periosteal in order releases, to obtain in ordera primary to obtain closure a primary of the surgicalclosure ofwound. the surgical Further wound. studies Furtherinvolving studies a larger involving sample aof larger patients sample with ofdifferent patients clinical with dipicturesfferent (differentclinical pictures types of (di BP,fferent dosage types and of route BP, dosage of administration; and route of multiple administration; tooth extractions multiple tooth with extractionsor without withsigns orof withoutinfection) signs will ofbe infection) necessary will to evaluate be necessary the success to evaluate rate and the the success predictability rate and theof this predictability technique inof preventing this technique BP-related in preventing osteonecrosis BP-related of the osteonecrosis jaw after tooth of the extraction. jaw after tooth extraction.

Author Contributions: conceptualization,Conceptualization, A.P.; A.P.; methodology, methodology, A.P.; A.P.; investigation, investigation, A.P. A.P. and I.B.; data curation, A.K. and D.S.; writing of original draf draftt preparation, I.B., I.B., A.K. A.K. and and D.S.; D.S.; writing writing of of review review and and editing, editing, E.M.V.; E.M.V.; visualization, A.P.; supervision,supervision, E.M.V.E.M.V. Funding: This research received no external funding. Funding: This research received no external funding.

Conflicts of Interest: The authors declare no conflicts of interest. Biomedicines 2019, 7, 89 7 of 8

Conﬂicts of Interest: The authors declare no conﬂicts of interest.

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